.beta.-phenylalanine is presently one of two ingredients, along with aspartic acid, that is used in the production of aspartame.
Ajinomoto, in 1974, received British Patent No. 1,377,900, dealing with a process in which phenylacetaldehyde was treated with ammonium, cyanide and carbonate ions at 122.degree.-302.degree. F. (50.degree.-150.degree. C.), and the intermediate was hydrolyzed at about 392.degree. F. (200.degree. C.) to produce phenylalanine. The yield was cited as 92.7%.
As recently as 1974, no established industrial method existed for L-phenylalanine production. Currently, both synthesis and fermentation have been investigated. Some of the chemical synthesis methods which have been reviewed by Kaneko et al. (See "Synthetic Production and Utilization of Amino Acids", Halsted Press, New York, 1974, p. 171-179) include using such starting materials as benzaldehyde, aniline, benzyl chloride, ethyl benzylacetoacetate, phenylacetaldehyde and L-tyrosine via various intermediates. Chemical synthesis of phenylalanine normally produces both the D- and L-phenylalanines, which must be resolved and separated. The D-phenylalanine is then racemized, and recycled for further recovery of the L-phenylalanine.
In 1983, Chimie Saline, a subsidiary of ENI was reported to be planning a plant to produce L-phenylalanine methyl ester directly from benzaldehyde, using technology developed by Assoreni, another ENI subsidiary. The process uses an asymmetric hydrogenating catalyst (see European Chem. News, July 18, 1983, p. 15). Phenylalanine is reportedly produced commercially from tyrosine, another amino acid that is isolated from hydrolyzates of natural proteins (see Chem. Mkt. Rep., May 14, 1984, p. 19).
While most current commercial production of L-phenylalanine is by fermentation (see SRI International Report No. 170, September 1984), other recent reports indicate that cinnamic acid can already be used economically to produce L-phenylalanine (European Chem. News, Oct. 29, 1984, p. 21).
The method most commonly used is fermentation, this employes a glucose substrate and a strain of Brevibacterium lactofermentum at 86.degree. F. (30.degree. C.) and a pH of 7.0. The product is collected from the cell-free broth by absorption on a strongly acidic cation exchange resin at a pH of about 2.0, eluted from the resin with dilute ammonium solution, precipitated and dried before it is esterified to L-phenylalanine methyl ester with an excess of methanol in the presence of a sulfuric acid.
There are a number of disclosures in the literature now dealing with the synthesis of .alpha.-amino acids and their derivatives using aldehydes as substrates in combination with amides and carbon monoxide.
U.S. Pat. No. 3,766,266 to H. Wakamatsu and J. Uda discloses a method of producing an N-acyl derivative of an .alpha.-amino acid which comprises holding an aldehyde, an amide of a carboxylic acid and carbon monoxide at a temperature of 10.degree. to 300.degree. C. and a pressure of at least 500 atm. in the presence of a carbonylation catalyst until said N-acyl-.alpha.-amino acid is formed.
In J. Chem. Soc. Chem. Comm. 1540 (1971), Wakamatsu, et al. disclose a cobalt-catalyzed carbonylation reaction which gives various N-acyl amino-acids from an aldehyde, an amide and carbon monoxide. In this disclosure, where phenylacetyladehyde was used as the starting aldehyde, the corresponding N-acetylphenylalanine was obtained in modest yield.
An article by Parnaud, et al., in Journal of Molecular Catalysis, 6 (1979) 341-350, discusses the synthesis potential and the catalytic mechanism for the amidocarbonylation reaction wherein N-acyl-.alpha.-amino acids are produced by reacting an aldehyde, CO and an amide in the presence of dicobalt octacarbonyl.
In amidocarbonylation, the aldehyde substrate can be generated in situ from allyl alcohol, alkyl halides, oxiranes, alcohols and olefins followed by the reaction with an amide and carbon monoxide to produce an N-acyl-.alpha.-amino acid.
U.S. Pat. No. 3,996,288 to Ajinomoto discloses that when an alcohol or certain of its ester derivatives is held at 50.degree. C. to 200.degree. C. and 10 to 500 atm. in the presence of hydrogen, carbon monoxide, the amide of a carboxylic acid, and a carbonylation catalyst, an aldehyde having one more carbon atom than the alcohol or ester is formed in good yield. If the amide has at least one active hydrogen atom on its amide nitrogen, it further reacts with the aldehyde and carbon monoxide to form an N-acylamino acid.
U.S. Pat. No. 4,264,515 by R. Stern et al. discloses a process for obtaining terminal N-acyl-.alpha.-amino acids by a reaction catalyzed by a cobalt carbonylation catalyst wherein the aldehyde is produced in situ from olefins and CO/H.sub.2 mixtures. An unsaturated vegetable oil or C.sub.8 -C.sub.30 monoolefinic compound is reacted with an amide, carbon monoxide and hydrogen in the presence of a cobalt catalyst. The process is operated in one step and provides for increased selectivity as compared to a two-step process.
A recent review article, published by I. Ojima et al. in Journal of Organometallic Chemistry, 279 (1985), 203-214, discusses the synthesis of N-acetyl-.alpha.-amino acids from (a) the isomerization-amidocarbonylation of allylic alcohols, (b) the isomerization-amidocarbonylation of oxiranes and (c) the hydroformylation-amidocarbonylation of trifluoropropene. This study contributes much data regarding regioselectivity for various products.
It would be an advance in the art to be able to use amidocarbonylation technology in the "key step" synthesis of .beta.-phenylalanine. It would appear that this could provide a less expensive route to phenylalanine. An inexpensive chemical building block such as styrene oxide could be rearranged to provide the phenylacetaldehyde substrate. A process which provided the phenylalanine precursor in good yield using mild reaction conditions would be especially desirable.
In the instant invention modified amidocarbonylation technology is used in the "key step" synthesis of .beta.-phenylalanine. N-acetylphenylalanine was prepared in ca. 82 mole % yield from the reaction of phenylacetaldehyde, acetamide and CO, by use of a dicobalt octacarbonyl catalyst.
Key features of the invention and distinctions from other work in the art include the following:
(1) The product selectivity is sensitive to the operating temperature. The results at 80.degree. C. are much better than those at 100.degree.-120.degree. C.
(2) The use of certain classes of cocatalyst has been found to stabilize the active cobalt species, as evidenced by cobalt recovery in product solution.